We propose to continue and expand our prospective study on the relationships between lifestyle factors and risk of amyotrophic lateral sclerosis (ALS). In our initial project, based on the follow-up of nearly one million participants in the Cancer Prevention Study II, we documented a 60% lower risk of ALS among men and women who reported regular use of vitamin E specific supplements as compared with non-users. This and other results which have important potential implications for the prevention of ALS need to be confirmed in a separate, large and rigorous prospective study. For this purpose, we plan to document ALS incidence and mortality infive large and well-established prospective cohorts - the Nurses'Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the Cancer Prevention Study II Nutrition (CPS UN),the Multiethnic Cohort (MEC), and the NIH-American Association of Retired Persons Diet and Health Study (AARP-DH)-- comprising a total of over one million men and women. Primary aims include the investigation of the associations between risk of ALS and use of antioxidant vitamins, non-steroidal anti-inflammatory drugs (NSAIDs) and cigarette smoking. In addition, we will explore the association between dietary factors and ALS risk. The main strengths of the proposed investigation are its prospective design and the availability of detailed, validated and updated exposure information in some of the cohorts. Further, by taking advantage of these cohorts with many years of follow-up already accumulated, we will be able with a modest budget and in a few years to achieve results which would otherwise require a much longer and moreexpensive investigation.